Project Summary Alzheimer?s disease (AD) causes progressive loss of memory, for which there is no cure. Although genetic studies initially suggested a primary role for amyloid-? (A?) in Alzheimer?s disease, treatment strategies targeted at reducing A? failed to reverse memory loss. A growing understanding of cognitive impairment in AD suggests that alterations at the genetic and cellular levels contribute to circuit dysfunction, which affects long- range network connectivity. Inhibitory interneuron dysfunction in the cortical and hippocampal regions has recently been implicated to contribute to memory deficits in the mouse models of AD. In this application, we will focus on a septo-hippocampal inhibitory network involving medial septum (MS) GABAergic projection neurons and hippocampal interneurons as a susceptibility node because septo-hippocampal GABAergic network is well- known to be responsible for generating hippocampal theta rhythm and is important for memory and cognition. Furthermore, our recent data demonstrated that selective ablation of MS GABAergic neurons leads to hippocampal network hyperexcitability and impaired hippocampal theta rhythm, two key features of AD, suggesting that loss of MS GABAergic neurons are necessary to cause hippocampal network dysfunction. Importantly, optogenetic activation of septo-hippocampal GABAergic projections in acute brain slices increases GABAergic inputs onto the hippocampal principle cells, suggesting that activation of septo-hippocampal GABAergic circuit might be able to counteract AD-associated hippocampal hyperexcitability. These data together suggest that septo-hippocampal GABAergic network may represent an AD-susceptible node thus playing critical roles in the pathophysiological and functional cascade of AD. We will test the overall hypothesis that septo-hippocampal GABAergic circuit connections are impaired in AD, and chronic stimulation of the septo-hippocampal GABAergic circuit can alleviate AD pathology, counteract hippocampal hyperexcitability, and restore hippocampal theta rhythm. We will use a triple transgenic mouse model of AD harboring Tau, PS2, and APP which has been shown to exhibit region and cell-type specific degeneration of GABAergic neurons in both MS and hippocampus. We will characterize the anatomical and functional connections of septo- hippocampal GABAergic network (Aim 1) and evaluate the effects of chronic septo-hippocampal circuit activation on AD pathology and hippocampal activity (Aim 2) using a combination of circuit-based tracing approaches and in vitro and in vivo electrophysiology. These studies will guide new therapeutic directions by selectively targeting AD-vulnerable neural circuits and network for treating memory loss.